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. 2021 Oct 30;26(21):6593.
doi: 10.3390/molecules26216593.

In Silico Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies

Mohamed S Alesawy  1 , Eslam B Elkaeed  2 , Aisha A Alsfouk  3 , Ahmed M Metwaly  4   5 , Ibrahim H Eissa  1
Affiliations

In Silico Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies

Mohamed S Alesawy et al. Molecules. .

Abstract

Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives 34 and 58 were better than the co-crystallized ligand while derivatives 17, 28, 31, 40, 41, 43, 47, 54, and 65 exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives 28, 34, and 47 have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of 28, 34, and 47 against the co-crystallized ligand in a DFT study indicated that 28 is the most promising candidate to interact with the target receptor (PLpro).

Keywords: ADMET; COVID-19; DFT; molecular docking; papain-like protease; pharmacophore; semi-synthesized; toxicity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Essential pharmacophoric features of SARS-CoV-2 PLPIs.
Figure 2
Figure 2
The chemical structures of the examined molecules.
Figure 2
Figure 2
The chemical structures of the examined molecules.
Figure 3
Figure 3
Representative sample of the examined semi-synthesized molecules having the main features of PLPIs.
Figure 4
Figure 4
Superimposition of the redocked pose colored in pink against the co-crystallized one colored in green (S88) in PLpro active site.
Figure 5
Figure 5
(A) 3D of S88 docked into the active site of PLpro. (B) 2D of S88 docked into the active site of PLpro. (C) Surface mapping of S88 docked into the active site of PLpro.
Figure 6
Figure 6
(A) 3D of compound 28 docked into the active site of PLpro. (B) 2D of compound 28 docked into the active site of PLpro. (C) Surface mapping of compound 28 docked into the active site of PLpro.
Figure 7
Figure 7
(A) 3D of compound 34 docked into the active site of PLpro. (B) 2D of compound 34 docked into the active site of PLpro. (C) Surface mapping of compound 34 docked into the active site of PLpro.
Figure 8
Figure 8
(A) 3D of compound 47 docked into the active site of PLpro. (B) 2D of compound 47 docked into the active site of PLpro. (C) Surface mapping of compound 47 docked into the active site of PLpro.
Figure 9
Figure 9
(A) 3D of compound 54 docked into the active site of PLpro. (B) 2D of compound 54 docked into the active site of PLpro. (C) Surface mapping of compound 54 docked into the active site of PLpro.
Figure 10
Figure 10
(A) 3D of compound 58 docked into the active site of PLpro. (B) 2D of compound 58 docked into the active site of PLpro. (C) Surface mapping of compound 58 docked into the active site of PLpro.
Figure 11
Figure 11
The expected ADMET study of the most potent semi-synthesized molecules.
Figure 12
Figure 12
Spatial distribution of molecular orbitals for (A) S88, (B) 28, and (C) 34, and (D) 47.
Figure 13
Figure 13
Molecular electrostatic potential map of (A) S88, (B) 28, and (C) 34, and (D) 47.
Figure 13
Figure 13
Molecular electrostatic potential map of (A) S88, (B) 28, and (C) 34, and (D) 47.
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